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Covid uses multiple "doors" to infect cells, not just the ACE2 receptor

A new study from UVA Health is challenging previous notions about how coronaviruses infect hosts across different species. The discovery sheds light on how COVID-19 infects cells and may allow scientists to better anticipate how the virus will evolve.

Focus of the study

Since the emergence of the COVID-19 pandemic, which has claimed nearly 7 million lives globally, scientists have been striving to understand how SARS-CoV-2 penetrates human cells. 

It was known that the virus targeted a specific protein called ACE2 found on human cells. The prevailing theory was that this protein acted as the sole entry point for the virus into the cells, especially those lining the nose and lungs.

What the researchers discovered 

“The virus that causes COVID-19 uses ACE2 as the front door to infect cells, but we’ve found that if the front door is blocked, it can also use the back door or the windows,” explained Dr. Peter Kasson.

“This means the virus can keep spreading as it infects a new species until it adapts to use a particular species’ front door. So we have to watch out for new viruses doing the same thing to infect us.”

Versatile virus

This discovery paints a picture of a virus far more versatile in its ability to infiltrate cells. It suggests that the virus does not rely solely on ACE2 but can utilize other proteins to enter cells. 

Although ACE2 is the most efficient route, it’s not the only one. The virus can bind and infect even cells without any ACE2 receptors.

This multiplicity of “doors” to enter cells could be the key to understanding why coronaviruses, including SARS-CoV-2, are adept at species-hopping. 

“Coronaviruses like SARS-CoV-2 have already caused one pandemic and several near misses that we know of. That suggests there are more out there, and we need to learn how they spread and what to watch out for,” said Dr. Kasson.

Implications of the study

While COVID-19 may no longer be the global threat it once was, thanks to vaccines and population immunity, the evolving nature of the virus and the potential for other coronaviruses to make the species jump mean scientists must remain vigilant.

The UVA findings could play a crucial role in future pandemic prevention strategies. By understanding the multiple pathways that these viruses can take to infect cells, researchers may be able to develop more targeted interventions and vaccines.

The study is published in the journal Chemical Science

More about how viruses infect cells

Viruses infect cells through a multi-step process, which generally includes the following stages:


Viruses begin the infection process by attaching to a host cell. The proteins on the surface of the virus bind to specific receptors on the surface of the host cell. This is often a highly specific interaction, like a lock and key, which determines the types of cells and species a particular virus can infect.


After binding to the receptor, the virus enters the host cell. This can occur through direct fusion with the host cell membrane or endocytosis, where the host cell engulfs the virus in a bubble-like vesicle.


Once inside the host cell, the viral coating is removed (uncoated), and the viral genome is released. This uncoating process can occur in various ways, depending on the type of virus.

Replication and transcription

The host cell’s machinery is then hijacked to replicate the viral genome and transcribe it into messenger RNA (mRNA). The mRNA is used by the host’s ribosomes to make viral proteins.


Newly made viral genomes and proteins are then assembled into complete, functional virus particles. This assembly takes place in specific parts of the cell, such as the endoplasmic reticulum or Golgi apparatus.

Budding and release

The newly assembled virus particles exit the host cell, often by budding off from the host cell’s membrane, taking a piece of the membrane with them to form their envelope. This release may or may not cause the destruction of the host cell, depending on the virus.

Infection of new cells

The new viral particles are now free to infect other cells and repeat the cycle.

Different viruses follow variations of this general pathway, depending on their structure and the type of host cell they infect. The details of each step can vary widely among different viruses. 

The ability to understand and interfere with this process is crucial for the development of antiviral drugs and vaccines.


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